Directed Antifungal Therapy for HIV-associated Cryptococcal Meningitis PI: Lad, Shivanand and McCabe, Aaron Project Summary Cryptococcosis is an important systemic mycosis and one of the most prevalent infectious diseases in human immunodeficiency virus (HIV)-positive individuals. Amongst the 25 million people with HIV/AIDS, recent estimates indicate that there are 1 million cases of CM globally per year, with 700,000 deaths per year. The mortality of HIV-associated CM remains unacceptably high, despite amphotericin B (AMB)-based therapy and access to antiretroviral therapy (ART). In addition to poor penetration and circulation of active antifungal therapies, elevated cerebrospinal fluid (CSF) opening pressure is another critical factor. The pathophysiology is thought to stem from a combination of high active CSF organism burden (1x106 CFU/ml) combined with obstruction of CSF outflow by organism and polysaccharide capsule along the arachnoid villi. Serial high volume lumbar punctures and other CSF diversion procedures can produce immediate symptom relief as well as reversing neurological morbidity. Minnetronix, a medical device development and manufacturing company, proposes this Phase I STTR in collaboration with experts from the Infectious Diseases and Neurosurgery Departments at Duke University. Phase I will focus on developing Neurapheresis, a cerebrospinal fluid (CSF) processing and drug delivery platform, that will rapidly clear specific pathogens for treating life threatening infections of the central nervous system (CNS). Importantly, continuous infusion of intrathecal AMB was recently suggested to clear infection more rapidly and completely, without the toxicities associated with intrathecal AMB boluses that have limited its clinical application. The objectives of the proposed project are to develop a system to deliver and circulate targeted antifungal therapies (AMB) directly to the CSF and evaluate drug concentration as well as organism burden in a CM animal model. In summary, Neurapheresis is an innovative therapeutic option that provides direct access to the CSF and creates active circulation combined with targeted pathogen removal. This treatment is intended to be complimentary and does not replace standard of care with systemic, intravenous antifungal regimens. Successful completion of this Phase I STTR will provide the data to justify broader preclinical studies and development of a GLP-quality system for treatment of CM in Phase II. Concurrent regulatory, clinical planning, and reimbursement work will be conducted to prepare for an investigational device exemption (IDE) application. The long-term goal of the project is to develop a novel fungicidal approach that rapidly reduces CSF fungal burden, morbidity and mortality for HIV-associated CM patients worldwide.